Endothelial shear stress signal transduction and atherogenesis: From mechanisms to therapeutics.

The endothelium is one of the largest organ systems in the body, and data continue to emerge regarding the importance of endothelial cell (EC) dysfunction in vascular aging and a range of cardiovascular diseases (CVDs). Over the last two decades and as a process intimately related to EC dysfunction, an increasing number of studies have also implicated endothelial to mesenchymal transition (EndMT) as a potentially disease-causal pathobiologic process that is involved in a multitude of differing CVDs. However, EndMT is also involved in physiologic processes (e.g., cardiac development), and transient EndMT may contribute to vascular regeneration in certain contexts. Given that EndMT involves a major alteration in the EC-specific molecular program, and that it potentially contributes to CVD pathobiology, the clinical translation opportunities are significant, but further molecular and translational research is needed to see these opportunities realized. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-physiol-032222-080806

Endothelial to Mesenchymal Transition in Health and Disease.

Myocardial injury as induced by myocardial infarction results in tissue ischemia, which critically incepts cardiomyocyte death. Endothelial cells play a crucial role in restoring oxygen and nutrient supply to the heart. Latest advances in single-cell multi-omics, together with genetic lineage tracing, reveal a transcriptional and phenotypical adaptation to the injured microenvironment, which includes alterations in metabolic, mesenchymal, hematopoietic and pro-inflammatory signatures. The extent of transition in mesenchymal or hematopoietic cell lineages is still debated, but it is clear that several of the adaptive phenotypical changes are transient and endothelial cells revert back to a naïve cell state after resolution of injury responses. This resilience of endothelial cells to acute stress responses is important for preventing chronic dysfunction. Here, we summarize how endothelial cells adjust to injury and how this dynamic response contributes to repair and regeneration. We will highlight intrinsic and microenvironmental factors that contribute to endothelial cell resilience and may be targetable to maintain a functionally active, healthy microcirculation. 

/pdf/why-is-endothelial-resilience-key-to-maintain-cardiac-health-h8xdzlsm.pdf

Why is endothelial resilience key to maintain cardiac health?

• Epithelium/endothelium on chips provides a novel and effective in vitro approach for interrogating human epithelium or endothelium pathophysiology. • Epithelium/endothelium on chips will promote the comprehension and treatment of common diseases of various organs. • The employment of patient-derived stem cells in chips can predict personalized therapeutic efficiency, contributing to the revolution of drug development. • The combination of different organs can facilitate the understanding of the interaction among organs and tumor metastasis. Epithelium and endothelium, occupying a significant proportion of cells in the human body, play a crucial role in maintaining organs’ normal structure and function. Various methods have been employed to study the physiology and pathology of epithelium and endothelium. However, these conventional methods, such as animal trials and two-dimensional (2D) cell culture, fail to precisely simulate the complex biology of the human body due to the species difference and lack of the native microenvironment in human systems, which is essential for cell culture. To overcome these limitations, epithelium/endothelium on chips have been proposed, which can mimic the pathophysiology of native human systems in a controllable way. This review introduces the recent progress in epithelium/endothelium on chips, aiming to provide a comprehensive review of the fabrication and application of this technology. We first depict the chips’ basic components, materials, and fabrication techniques. Then, we focus on different chip types, from single cell-on-chip, single organ/tissue-on-chip, to multi-organs-on-chip. After that, we describe the biomedical applications such as in vitro study of the physiology and interaction of organs, construction of disease models, and drug development. Finally, the recent challenges and future outlook of epithelium/endothelium on chips are discussed. 

Biomimetic epithelium/endothelium on chips

The core of the drug research and screening processes is predicting the effect of drugs prior to human clinical trials. Due to the 2D cell culture and animal models' poor predictability, the cost of drug discovery is continuously rising. The development of organ-on-a-chip technology, an alternative to traditional preclinical drug testing models, resulted from the intersection of microfabrication & tissue engineering. Preclinical safety and effectiveness testing is improved by the ability of organ-on-a-chip technologies to mimic important human physiological functions necessary for understanding drug effects. Organ-on-a-chip could drastically improve the success rate of the preclinical testing thereby better predicting how the drug will act on the clinical trials. Organ-on-a-chip is a term used to describe a microengineered biomimetic device that mimics the structure and functionality of human tissue. It integrates engineering, cell biology, & biomaterial technologies on a miniature platform. To reflect human physiology in vitro and bridge the gap between in vivo and in vitro data, simplification shouldn't compromise physiological relevance. At this level of organ-on-a-chip technological development, biomedical engineers specializing in device engineering are more important than ever to expedite the transfer of technology from the academic lab bench to specialized product development institutions and an ever-growing market. This review focuses on the recent advancements in the organ-on-a-chip technology and discusses the potential of this technology based on the current available literature. • Organ-on-a-chip technologies allow drug testing without using animal models. • Organ-on-a-chip can accelerate the preclinical research in the drug discovery process. • Disease physiology and pathogenesis could be simulated using organ-on-a-chip device. • Animal research may not be as accurate as experiments on real human tissue. 

Organ-on-a-chip microengineering for bio-mimicking disease models and revolutionizing drug discovery

A three-dimensional microengineered human coronary artery-on-a-chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells (ECs) including pro-inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK-NF-κB signaling axis. Moreover, OSS-induced EC phenotypic changes resulted in proliferation and extracellular matrix (ECM) protein up-regulation in smooth muscle cells (SMCs) through the RANTES-mediated paracrine mechanism. IL-37 suppressed OSS-induced pro-inflammatory EndMT and thereby abrogated SMC proliferation and ECM protein remodeling. Overall, this study provides insights into endothelial heterogeneity under atheroprone shear stress and identifies the mechanistic role of a novel EC subtype in promoting adverse vascular remodeling. Further, this study demonstrates that anti-inflammatory approach is capable of mitigating vascular pathobiology evoked by atheroprone shear stress.

http://advances.sciencemag.org/content/advances/7/34/eabg1694.full.pdf

Peng Zhao

Papers

Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip